Alterations in serotonin (5-HT) receptor and transporter (SERT) activity may play a key role in the pathogenesis and treatment of major depressive episode (MDE). SERT sites are strategically located in brain regions that may play a role in modulating mood and affect. Recent brain imaging studies suggest that altered central 5-HT activity in MDE may be reflected in reduced midbrain SERT levels, and that this disturbance may "normalize" with clinical improvement. We have recently shown a significant reduction in midbrain SERT levels in MDE patients vs. healthy controls (p<0.01) using 123I ADAM SPECT imaging. This grant proposal seeks to: (i) confirm our initial findings of reduced midbrain SERT levels in MDE patients vs. healthy controls;and, (ii) to determine if reduced midbrain SERT levels represent a state-dependent biomarker of MDE that "normalizes" with response to antidepressant therapy. We propose using 123I ADAM SPECT and MRI co-registration to measure midbrain SERT activity in MDE patients before and after treatment with cognitive behavior therapy (CBT), and compare these results with SERT levels in healthy controls studied on two separate occasions. For specific aim #1 we will ask: Do reduced midbrain SERT levels represent a bio-marker of MDE compared to non-depressed, healthy controls? For specific aim #2 we will ask: Do reduced midbrain SERT levels represent a state-dependent biomarker of MDE that "normalizes" in MDE patients who respond to CBT vs. patients who do not respond to CBT? We will also ask: Do midbrain SERT levels remain stable over time in healthy control subjects studied on two separate occasions? To answer question #1, we will measure midbrain SERT levels using 123I ADAM SPECT and MRI co-registration in drug naive MDE patients and in healthy controls. This will represent confirmatory data of our preliminary observations with 123I ADAM SPECT. We hypothesize that SERT levels will be reduced in MDE patients vs. healthy controls. To answer question #2, we will measure SERT levels in drug naive MDE patients before and after 12 weeks of CBT, and we will also measure SERT levels in healthy controls on two separate occasions 12 weeks apart. We hypothesize that reduced SERT levels in MDE patients will increase after response to CBT, and will not appreciably change in patients who do not respond to CBT. We further hypothesize that midbrain SERT levels will remain stable over time in non-depressed, healthy control subjects.